Rgd peptide attached to bioabsorbable stents

ABSTRACT

Provided herein is a method of forming medical device that includes RGD attached to the device via a spacer compound. The method comprises providing a spacer compound comprising a hydrophobic moiety and a hydrophilic moiety, grafting or embedding the spacer compound to the surface layer of the polymer to cause the hydrophobic moiety to be grafted to or embedded within the surface layer of polymer, and attaching a chemo-attractant to the hydrophilic moiety.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. Ser. No. 11/453,679filed Jun. 14, 2006. The aforementioned patent application isincorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

This invention is generally related to bioabsorbable devices having RGDattached thereto.

2. Description of the State of the Art

Percutaneous coronary intervention (PCI) is a procedure for treatingheart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress theatherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

Problems associated with the above procedure include formation ofintimal flaps or torn arterial linings which can collapse and occludethe blood conduit after the balloon is deflated. Moreover, thrombosisand restenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of the arterial lining and to reduce the chanceof thrombosis or restenosis, a stent is implanted in the artery to keepthe artery open.

Drug delivery stents have reduced the incidence of in-stent restenosis(ISR) after PCI (see, e.g., Serruys, P. W., et al., J. Am. Coll.Cardiol. 39:393-399 (2002)), which has plagued interventional cardiologyfor more than a decade. However, ISR still poses a significant problemgiven the large volume of coronary interventions and their expandinguse. The pathophysiological mechanism of ISR involves interactionsbetween the cellular and acellular elements of the vessel wall and theblood. Damage to the endothelium during PCI constitutes a major factorfor the development of ISR (see, e.g., Kipshidze, N., et al., J. Am.Coll. Cardiol. 44:733-739 (2004)).

The polypeptide Arg-Gly-Asp (RGD) has been demonstrated to be abioactive factor for human endothelial cell attachment. It also has beenshown that on a polymer surface having RGD chemically bonded to thesurface, the growth rate of human endothelial cells can be increased(see, Ruoslahti, E., et al. Science 238:491-497 (1987)). However, thisstudy fails to take into account the accessibility of the RGD to theendothelial progenitor cells (EPCs) so that the endothelial cell growthenhancing effect described therein is limited.

Therefore, there is a need for an attractant attached to a surface forendothelial progenitor cells.

There is a further need for an attractant attached to a surface thatprovides for improved accessibility of the attractant.

The embodiments of the present invention address these concerns as wellas others that are apparent to one having ordinary skill in the art.

SUMMARY

Provided herein is a method of forming a medical device, an example ofwhich is a stent such as a bioabsorbable stent, comprising achemo-attractant attached to a surface layer of polymer on the medicaldevice including a chemo-attractant for endothelial progenitor cells(EPCs). The method comprises providing a spacer compound comprising ahydrophobic moiety and a hydrophilic moiety, grafting or embedding thespacer compound to the surface layer of the polymer to cause thehydrophobic moiety to be grafted to or embedded within the surface layerof polymer, and attaching a chemo-attractant to the hydrophilic moiety.The chemo-attractant is chemically bonded to the bioabsorbable stent viaa spacer compound. In some embodiments, the spacer compound comprises ahydrophobic moiety and a hydrophilic moiety. The spacer compound can begrafted to the surface of the bioabsorbable stent. The hydrophobicmoiety can be embedded in the stent, and the chemo-attractant can beattached to the hydrophilic moiety. Upon implantation, the hydrophilicmoiety can be projected from the surface of the medical device toward aphysiologic environment. The chemo-attractant can then recruit EPCs soas to enhance the growth rate of endothelium on the surface of thedevice. It is important to note that a linker of this construct allowsfor more freedom for EPCs to access to the chemo-attractant so that theregeneration rate of endothelium on the surface can be enhanced.

In some embodiments, the medical device described herein can furtherinclude a bioactive agent. Some examples of the bioactive agent include,but are not limited to, paclitaxel, docetaxel, estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, mometasone, CD-34 antibody, abciximab(REOPRO), progenitor cell capturing antibody, prohealing drugs, prodrugsthereof, co-drugs thereof, or a combination thereof.

The medical device described herein can be formed on a medical devicefor treating, preventing, or ameliorating a medical condition such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation (for vein andartificial grafts), bile duct obstruction, ureter obstruction, tumorobstruction, or combinations of these.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a three-dimensional conformation of DMPE-PEG 3000(1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-3000])

DETAILED DESCRIPTION

Provided herein is a bioabsorbable stent including a chemo-attractantfor endothelial progenitor cells (EPCs). The chemo-attractant ischemically bonded to the bioabsorbable stent via a spacer compound. Insome embodiments, the spacer compound comprises a hydrophobic moiety anda hydrophilic moiety. The spacer compound can be grafted to the surfaceof the bioabsorbable stent. The hydrophobic moiety can be embedded inthe stent, and the chemo-attractant can be attached to the hydrophilicmoiety. Upon implantation, the hydrophilic moiety can be projected fromthe surface of the medical device toward a physiologic environment. Thechemo-attractant can then recruit EPCs so as to enhance the growth rateof endothelium on the surface of the device. It is important to notethat a spacer compound of the present invention allows for more freedomfor EPCs to access to the chemo-attractant so that the regeneration rateof endothelium on the surface can be enhanced.

In some embodiments, the medical device described herein can include abioactive agent. Some examples of the bioactive agent include siRNAand/or other oligonucleotides that inhibit endothelial cell migration.The bioactive agent can also be lysophosphatidic acid (LPA) orsphingosine-1-phosphate (S1P). LPA is a “bioactive” phospholipid able togenerate growth factor-like activities in a wide variety of normal andmalignant cell types. LPA plays an important role in normalphysiological processes such as wound healing, and in vascular tone,vascular integrity, or reproduction. Some other exemplary bioactiveagents are paclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitricoxide donors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), biolimus,tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), ÿ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugsthereof, and combinations thereof.

The bioactive agents that can be included in a coating with thechemo-attractant described herein can be any bioactive agents. Someexamples of the bioactive agent include siRNA and/or otheroligonucleotides which inhibit migration of endothelial cells. Thebioactive agent can also be lysophosphatidic acid (LPA) andsphingosine-1-phosphate (S1P). LPA is a “bioactive” phospholipid able togenerate growth factor-like activities in a wide variety of normal andmalignant cell types. LPA plays an important role in normalphysiological situations such as wound healing, vascular tone, vascularintegrity, or reproduction. Some other exemplary bioactive agents arepaclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), ÿ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, midostaurin, prodrugs thereof, co-drugsthereof, and combinations thereof. The medical device such as a stent,can be implanted in a patient to treat, prevent, mitigate, or reduce avascular medical condition, or to provide a pro-healing effect. Examplesof these conditions include atherosclerosis, thrombosis, restenosis,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation (for vein and artificial grafts), bile duct obstruction,ureter obstruction, tumor obstruction, or combinations of these. Thecoating can be formed on an implantable device such as a stent, whichcan be implanted in a patient to treat, prevent, mitigate, or reduce avascular medical condition such as atherosclerosis, thrombosis,restenosis, hemorrhage, vascular dissection or perforation, vascularaneurysm, vulnerable plaque, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, pro-healing thereof,or combinations thereof and/or pro-healing.

Chemo-Attractants

As used herein, the chemo-attractant includes any synthetic or naturalmolecules capable of attracting endothelial cells. In some embodiments,the chemo-attractant includes any synthetic or natural molecules capableof attracting an effective number of endothelial cells. The attractantgenerally has a degree of selectivity towards. The chemo-attractant alsoincludes any synthetic or natural molecules capable of binding toadhesion receptors differentially expressed on the endothelial cells.One such adhesion receptor can be integrin. Some exemplarychemo-attractants include, but are not limited to, smallintegrin-binding molecules, RGD peptide or cyclic RGD peptide (cRGD),synthetic cyclic RGD (cRGD) mimetics, and small molecules binding toother adhesion receptors differentially expressed on the endothelialcells.

In some embodiments, the chemo-attractant can be those molecules capableof binding to ICAM (intercellular adhesion molecule) molecules or VCAM(vascular cell adhesion molecule) molecules, which are present in theendothelial cells. Such chemo-attractant can be, for example, receptorsbinding to ICAM or VCAM in the endothelial cells, which can include, butare not limited to, Decoy receptor 3 (DcR3), a tumor necrosis factor(TNF) that preferentially binds to ICAM and VCAM_(—)2, integrin LFA-1(LFA-1Af) (expressed on lymphocytes), which has conformational changesin extracellular domains enabling higher affinity binding to the ligandICAM-1, or combinations thereof.

In some embodiments, the chemo-attractant can specifically exclude aparticular chemo-attractant described above.

cRGD or RGD Mimetics

The cRGD or RGD mimetics described herein includes any peptides orpeptide mimetics that result from the modification of the cyclicArg-Gly-Asp peptide. The modification can be on the pendant groupsand/or on the backbone of the peptide. Peptide synthesis, including thesynthesis of peptide mimetics, is well documented and can be readilyachieved using, for example, combinatorial chemistry.

Some examples of cRGD or RGD mimetics include v3 antagonists such asIIb/IIIb antagonists (Coller, B. S., Thromb. Haemost. 86(1):427-43(2001) (Review)), one example of which is Abciximax (Blindt, R., J. Mol.Cell. Cardiol. 32:2195-2206 (2000)), XJ 735 (Srivatsa, S. S., et al.,Cardiovasc. Res. 36:408-428 (1997)), anti-b3-integrin antibody F11, cRGD(Sajid, M., et al., Am. J. Physiol. Cell Physiol., 285:C1330-1338(2003), and other sequences such as laminin derived SIKVAV (Fittkau, M.H., et al., Biomaterials, 26:167-174 (2005)), laminin derived YIGSR(Kouvroukoglou, S., et al., Biomaterials, 21:1725-1733 (2000)), KQAGDV,and VAPG (Mann, B. K., J. Biomed. Mater. Res. 60(1):86-93 (2002)). Thefollowing describes a basic procedure for the synthesis of a peptide,including a peptide mimetics:

Before the peptide synthesis starts, the amine end of the amino acid(starting material) is protected with FMOC (9-fluoromethyl carbamate) orother protective groups, and a solid support such as a Merrifield resin(free amines) is used as an initiator. Then, step (1) through step (3)reactions are performed and repeated until the desired peptide isobtained: (1) a freeamine is reacted with the carboxyl end usingcarbodiimide chemistry, (2) the amino acid sequence is purified, and (3)the protecting group, e.g., the FMOC protecting group, is removed undermildly acidic conditions to yield a free amine. The peptide can then becleaved from the resin to yield a free standing peptide or peptidemimetic.

In some embodiments, a coating can specifically exclude any of the abovementioned chemo-attractant. For example, a coating can specificallyexclude RGD peptide or cyclic RGD peptide (cRGD).

Spacer Compounds

In some embodiments, the spacer compound can have a phospholipid moietyas the hydrophobic moiety. Any phospholipid can be incorporated into thespacer compound. For example, the phospholipid can bephosphatidylcholine, phosphatidylethanolamine, phosphatidic acid,phosphatidylserine, phosphatidylglycerol, cardiolipin, orphosphatidylinositol.

In some embodiments, the spacer compound can have a hydrophilic moietywhich is PEG. In these embodiments, the hydrophobic moiety of the spacercompound can be grafted to or embedded within the surface of the medicaldevice. Upon placed in a physiological environment, the PEG moiety canproject from the surface to allow attachment of a chemo-attractant tothe PEG moiety. For example, the spacer compound can have a structure of

which is DMPE-PEG 3000. Conformational studies on DMPE-PEG 3000 showedthat this molecule has a bulk PEG head group and a relatively smallphospholipids tail (FIG. 1).

The PEG moiety can have different molecular weights. Generally, themolecular weight of PEG shall be below about 20,000 Daltons so as toallow the PEG to be excreted from the body. Some exemplary ranges of themolecular weight of PEG can be from about 300 Daltons to about 15,000Daltons, about 1000 Daltons to about 10,000 Daltons, about 2000 Daltonsto about 5000 Daltons or about 4000 Daltons.

In some embodiments, the spacer compound can be a di-block copolymerthat includes a polymeric hydrophobic block and a polymeric hydrophilicblock having a general formula of [hydrophobicpolymer]-block-[hydrophilic polymer]. The hydrophobic block can be anyhydrophobic polymer. In some embodiments, the hydrophobic polymer can beselected from poly(ester amide), polyhydroxyalkanoates (PHA),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers including any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),polycaprolactone, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,polyphosphazenes, silicones, polyesters, polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers, acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride,polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidenehalides, such as polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters,such as polyvinyl acetate, copolymers of vinyl monomers with each otherand olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers, polyamides, such as Nylon 66 and polycaprolactam, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers,poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butylmethacrylate), poly(sec-butyl methacrylate), poly(isobutylmethacrylate), poly(tert-butyl methacrylate), poly(n-propylmethacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate),poly(methyl methacrylate), polyurethanes, polyalkylene oxalates,polyphosphazenes, or poly(aspirin). In some embodiments, the copolymerdescribed herein can exclude any one of the aforementioned polymers.

The hydrophobic moiety and the hydrophilic moiety shall have a molecularweight or degrade into fragments having a molecular weight ranging fromabout 20,000 Daltons so as to allow the PEG to be excreted from thebody. For example, such a di-block copolymer can bepoly(L-lactide-co-PEG (3000)).

In some embodiments, the spacer compound can include other hydrophilicmoieties. For example, such other hydrophilic moieties can be,poly(alkylene oxide), poly(vinyl alcohol) or poly(ethylene glycol).

Attaching Chemo-Attractant to Hydrophilic Moiety

The chemo-attractant can be attached to the spacer compound describedherein via a linkage. The linkage can be degradable or non-degradable.Degradable linkages can be hydrolytically degradable linkages orenzymatically degradable linkages. A hydrolytically degradable linkagecan link the chemo-attractant and the spacer compound via the linkage'sreactive groups. For example, in some embodiments, the linkage can be anamino acid group that includes amino, thiol, and/or carboxylic groups.Some exemplary strategies for forming hydrolytically degradable linkagesinclude:

(1) ε-Amino group of lysine (which can be integrated into a polymer) andα-amino group of a protein. The amine can be on the polymer backbone(with or without a spacer compound, e.g., PEG, or an alkyl chain). Thiscan yield an amide, thiourea, alkylamine or urethane linkage.

(2) Thiol group or a free cysteine, which forms a thioether linkage.

(3) Thiol group on a cysteine, which can be conjugated with vinylsulfone(R—SO₂—CH═CH₂).

(4) Carboxylic acid groups on the aspartic and glutamic acid.

Some examples of hydrolytically degradable linkages include amidelinkages that can be generated by reacting an amine group with succinateesters such as N-hydroxysuccinimide (NHS), thiol linkages such asdisulfide (R-L1-S—S-L2-R′) where the length of the linker L1 and L2control the hydrolization, or ester bonds formed by coupling thepeptide's carboxylic end with a hydroxyl on the polymer backbone (withor without a spacer compound, e.g., PEG, or an alkyl chain).Esterification can be carried out using established methods in the art(e.g., carbodiimide chemistry in the presence of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)).

Enzymatically degradable linkages can be degraded by an enzyme, often totarget a specific area of the body or organ. In other words, thestimulus for an enzymatically degradable linkage is the presence of anenzyme. For example, a specific dipeptide sequence can be incorporatedinto the linkage, which can be cleaved by an enzyme. Some examples ofenzymatically degradable linkages include, but are not limited to,self-immolative p-aminobenzyloxycarbonyl (PABC) spacer compound betweenthe dipeptide and the polymer, dipeptides such as phenylaniline-lysineand valine-cysteine, or PEG/dipeptide linkages such as alanyl-valine,alanyl-proline and glycyl-proline.

In some embodiments, the chemo-attractant can be attached to thehydrophilic moiety in the spacer compound by using a photosensitivemoiety. In some embodiments, the photosensitive moiety can be, e.g.,(N-succinimidyl-6-[4′-azido-2′-nitrophenylamino]-hexanoate). An exampleof using this photosensitive moiety to attach RGD to PEG is described byChung et al., J. Biomed. Mater. Res. Part A, vol. 72A(2):213-219 (2005).

Some other linkages can be found at “Biodegradable Polymers for Proteinand Peptide Drug Delivery” Bioconjugate Chem. 1995, 6:332-351; M. P.Lutolf and J. A. Hubbell, Biomacromolecules 2003, 4:713-722; and U.S.patent application Ser. No. 10/871,658. Some additional representativelinking chemistry is described in U.S. patent application Ser. No.10/871,658, the entire disclosure of which is hereby incorporated byreference.

Attaching the Spacer Compound to Medical Device

The chemo-attractant can be attached to the spacer compound describedprior to or after the spacer compound is applied to the surface of themedical device. In some embodiments, the spacer compound can be appliedto the surface of the medical device prior to the surface attachment ofthe chemo-attractant to the spacer compound. In some embodiments, thespacer compound can be applied to the surface of a medical device afterthe chemo-attractant is attached to the spacer compound.

The spacer compound can be applied to the surface of a bioabsorbablemedical device by an established method of forming a coating. Forexample, spacer compound can be spray coated onto the surface of amedical device (e.g., a bioabsorbable stent). The spacer compound willthen phase separate, with the hydrophobic moiety of the spacer compoundbeing embedded within the surface layer of the medical device and thehydrophilic moiety projecting from the surface of the medical device.

The embedding of the hydrophobic moiety of the spacer compound can beachieved by using an appropriate solvent in coating the spacer compound.For example, the solvent can be chosen so that it can dissolve thespacer compound and dissolve, swell or plasticize a polymer on thesurface of the medical device, which can be a coating surface or surfaceof the medical device itself. The solvent provides the opportunity forthe hydrophobic moiety of the spacer compound to entangle with or embedwithin the top layer of the dissolved, swelled, or plasticized surfaceof the medical device. The solvent can be a single solvent or a mixtureof solvents. In the mixture of solvents, the solvents shall be mutuallymiscible or substantially miscible. In some embodiments, the solvent canbe a mixture of a solvent for the spacer compound and a solvent for apolymer on the surface of the medical device.

Grafting the spacer compound to the medical device can be achieved bythe methods revealed in Nam, Y, et al. Biotechnology letters 2093-98(2002).

In some embodiments, the spacer compound can be attached, embedded orgrafted to the surface of a medical device after the chemo-attractanthas been attached to the spacer compound via the linkage describe above.The spacer compound with the chemo-attractant can be the spray coatedonto the surface of a medical device as described above.

Biocompatible Polymers

The medical device having the features described herein can include anybiocompatible polymer. The biocompatible polymer can be biodegradable(both bioerodable or bioabsorbable) or nondegradable and can behydrophilic or hydrophobic.

Representative biocompatible polymers include, but are not limited to,poly(ester amide), polyhydroxyalkanoates (PHA),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers including any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),polycaprolactone, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,polyphosphazenes, silicones, polyesters, polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers, acrylic polymers and copolymers,vinyl halide polymers and copolymers, such as polyvinyl chloride,polyvinyl ethers, such as polyvinyl methyl ether, polyvinylidenehalides, such as polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polyvinyl aromatics, such as polystyrene, polyvinyl esters,such as polyvinyl acetate, copolymers of vinyl monomers with each otherand olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers, polyamides, such as Nylon 66 and polycaprolactam, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers,poly(glyceryl sebacate), polypropylene fumarate), poly(n-butylmethacrylate), poly(sec-butyl methacrylate), poly(isobutylmethacrylate), poly(tert-butyl methacrylate), poly(n-propylmethacrylate), poly(isopropyl methacrylate), poly(ethyl methacrylate),poly(methyl methacrylate), epoxy resins, polyurethanes, rayon,rayon-triacetate, cellulose acetate, cellulose butyrate, celluloseacetate butyrate, cellophane, cellulose nitrate, cellulose propionate,cellulose ethers, carboxymethyl cellulose, polyethers such aspoly(ethylene glycol) (PEG), copoly(ether-esters) (e.g. poly(ethyleneoxide/poly(lactic acid) (PEO/PLA)), polyalkylene oxides such aspoly(ethylene oxide), poly(propylene oxide), poly(ether ester),polyalkylene oxalates, polyphosphazenes, phosphoryl choline, choline,poly(aspirin), polymers and co-polymers of hydroxyl bearing monomerssuch as 2-hydroxyethyl methacrylate (HEMA), hydroxypropyl methacrylate(HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEGmethacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinylpyrrolidone (VP), carboxylic acid bearing monomers such as methacrylicacid (MA), acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as chitosan, alginate, fibrin, fibrinogen, cellulose,starch, dextran, dextrin, fragments and derivatives of hyaluronic acid,heparin, fragments and derivatives of heparin, glycosamino glycan (GAG),GAG derivatives, polysaccharide, chitosan, alginate, or combinationsthereof. In some embodiments, the copolymer described herein can excludeany one of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

In some embodiments, the surface layer of the medical device can includea biobeneficial material. The combination can be mixed, blended, orpatterned or arranged in separate layers. The biobeneficial materialuseful in the coatings described herein can be polymeric ornon-polymeric. The biobeneficial material is preferably non-toxic,non-antigenic and non-immunogenic enough so that it can be successfullyintroduced into a patient. A biobeneficial material is one whichenhances the biocompatibility of a device by being non-fouling,hemocompatible, actively non-thrombogenic, or anti-inflammatory, allwithout depending on the release of a pharmaceutically active agent.

Representative biobeneficial materials include, but are not limited to,polyethers such as poly(ethylene glycol), copoly(ether-esters),polyalkylene oxides such as poly(ethylene oxide), poly(propylene oxide),poly(ether ester), polyalkylene oxalates, polyphosphazenes, phosphorylcholine, choline, poly(aspirin), polymers and co-polymers of hydroxylbearing monomers such as hydroxyethyl methacrylate (HEMA), hydroxypropylmethacrylate (HPMA), hydroxypropylmethacrylamide, poly (ethylene glycol)acrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic-acid-bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as fibrin, fibrinogen, cellulose, starch, dextran,dextrin, hyaluronic acid, fragments and derivatives of hyaluronic acid,heparin, fragments and derivatives of heparin, glycosamino glycan (GAG),GAG derivatives, polysaccharide, chitosan, alginate, silicones,POLYACTIVE, and combinations thereof. In some embodiments, the coatingcan exclude any one of the aforementioned polymers.

The term POLYACTIVE refers to a block copolymer having flexiblepoly(ethylene glycol) and poly(butylene terephthalate) blocks(PEGT/PBT). POLYACTIVE is intended to include AB, ABA, BAB copolymershaving such segments of PEG and PBT (e.g., poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol)(PEG-PBT-PEG).

Bioactive Agents

In some embodiments, the medical device having the features describedherein can optionally include one or more bioactive agents. Thesebioactive agents can be any agent which is a therapeutic, prophylactic,or diagnostic agent. These agents can have anti-proliferative oranti-inflammatory properties or can have other properties such asantineoplastic, antiplatelet, anti-coagulant, antifibrin,antithrombonic, antimitotic, antibiotic, antiallergic, or antioxidantproperties.

These agents can be cystostatic agents, agents that promote the healingof the endothelium (other than by releasing or generating NO), or agentsthat promote the attachment, migration and proliferation of endothelialcells while quenching smooth muscle cell proliferation. Examples ofsuitable therapeutic and prophylactic agents include synthetic inorganicand organic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Nucleic acidsequences include genes, antisense molecules, which bind tocomplementary DNA to inhibit transcription, and ribozymes. Some otherexamples of bioactive agents include antibodies, receptor ligands,enzymes, adhesion peptides, blood clotting factors, inhibitors or clotdissolving agents, such as streptokinase and tissue plasminogenactivator, antigens for immunization, hormones and growth factors,oligonucleotides such as antisense oligonucleotides and ribozymes andretroviral vectors for use in gene therapy. Examples ofanti-proliferative agents include rapamycin and its functional orstructural derivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),and its functional or structural derivatives, paclitaxel and itsfunctional and structural derivatives. Examples of rapamycin derivativesinclude ABT-578, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), super oxide dismutases, superoxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements suchas various vitamins, and a combination thereof. Examples ofanti-inflammatory agents including steroidal and non-steroidalanti-inflammatory agents include biolimus, tacrolimus, dexamethasone,clobetasol, corticosteroids or combinations thereof. Examples of suchcytostatic substance include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, and genetically engineered epithelial cells. The foregoingsubstances can also be used in the form of prodrugs or co-drugs thereof.The foregoing substances also include metabolites thereof and/orprodrugs of the metabolites. The foregoing substances are listed by wayof example and are not meant to be limiting. Other active agents whichare currently available or that may be developed in the future areequally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than the level atwhich non-therapeutic results are obtained. The dosage or concentrationof the bioactive agent can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutically effective dosages can be determined empirically, forexample by infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies. Standard pharmacological test procedures to determine dosagesare understood by those of ordinary skill in the art.

Examples of Implantable Device

As used herein, an implantable device can be any suitable medicalsubstrate that can be implanted in a human or veterinary patient.Examples of such implantable devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),heart valve prosthesis (e.g., artificial heart valves) or vasculargraft, cerebrospinal fluid shunts, pacemaker electrodes, catheters,endocardial leads (e.g., FINELINE and ENDOTAK, available from GuidantCorporation, Santa Clara, Calif.), and devices facilitating anastomosissuch as anastomotic connectors. The underlying structure of the devicecan be of virtually any design. The device can include a metallicmaterial or an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention. The device can be, forexample, a bioabsorbable stent.

Method of Use

In accordance with embodiments of the invention, a chemo-attractant canbe attached to a medical device or prosthesis, e.g., a stent. For adevice including one or more active agents, the agent will retain on thedevice such as a stent during delivery and expansion of the device, andreleased at a desired rate and for a predetermined duration of time atthe site of implantation.

Preferably, the device is a stent. The stent described herein is usefulfor a variety of medical procedures, including, by way of example,treatment of obstructions caused by tumors in the bile ducts, esophagus,trachea/bronchi and other biological passageways. A stent having theabove-described coating is particularly useful for treating occludedregions of blood vessels caused by abnormal or inappropriate migrationand proliferation of smooth muscle cells, thrombosis, and restenosis.Stents may be placed in a wide array of blood vessels, both arteries andveins. Representative examples of sites include the iliac, renal, andcoronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter that allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of forming a medical device comprising a chemo-attractantattached to a surface layer of polymer on the medical device, comprisingproviding a spacer compound comprising a hydrophobic moiety and ahydrophilic moiety, grafting or embedding the spacer compound to thesurface layer of the polymer to cause the hydrophobic moiety to begrafted to or embedded within the surface layer of polymer, andattaching a chemo-attractant to the hydrophilic moiety.
 2. The method ofclaim 1 wherein the hydrophobic moiety comprises a phospholipid.
 3. Themethod of claim 2 wherein the phospholipid comprisesdistearoylphosphatidylethanolamine (DSPE) or1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE).
 4. The methodof claim 1 wherein the spacer compound is DMPE-PEG.
 5. The method ofclaim 1 wherein the spacer compound is a di-block copolymer, wherein thehydrophobic moiety comprises a hydrophobic polymer block, and whereinthe hydrophilic moiety comprises a hydrophilic polymer block.
 6. Themethod of claim 5 wherein the hydrophobic polymer block comprisespoly(lactic acid).
 7. The method of claim 6 wherein the hydrophilicpolymer block comprises PEG, poly(alkylene oxide), poly(vinyl alcohol)or combinations of these.
 8. The method of claim 5 wherein thehydrophilic polymer block comprises PEG, poly(alkylene oxide),poly(vinyl alcohol) or combinations of these.
 9. The method of claim 5wherein the spacer compound is poly(L-lactide-co-PEG (3000)).
 10. Themethod of claim 1 wherein the hydrophobic moiety comprises a hydrophobicpolymer block.
 11. The method of claim 2 wherein the hydrophilic moietycomprises PEG.
 12. The method of claim 10 wherein the hydrophilic moietycomprises PEG.
 13. The method of claim 12 wherein the chemo-attractantis selected from RGD, cRGD, mimetics thereof, or combinations of these.14. The method of claim 13 wherein the medical device is a bioabsorbablestent.
 15. The method of claim 14 wherein the medical device furthercomprising a bioactive agent.
 16. The method of claim 15 wherein thebioactive agent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutses, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.
 17. The method of claim 12wherein the chemo-attractant comprises Decoy receptor 3 (DcR3) orintegrin LFA-1 (LFA-1Af).
 18. The method of claim 17 further comprisinga bioactive agent.
 19. The method of claim 18 wherein the bioactiveagent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutses, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.
 20. The method of claim 12wherein the chemo-attractant comprises a receptor binding to ICAM(intercellular adhesion molecule) molecules or VCAM (vascular celladhesion molecule) molecules present in the endothelial cells.
 21. Themethod of claim 20 wherein the medical device is a bioabsorbable stent.22. The method of claim 1 wherein the chemo-attractant is selected fromRGD, cRGD, mimetics thereof, or combinations of these.
 23. The method ofclaim 1 wherein the chemo-attractant comprises Decoy receptor 3 (DcR3)or integrin LFA-1 (LFA-1Af).
 24. The method of claim 23 furthercomprising a bioactive agent.
 25. The method of claim 24 wherein thebioactive agent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutses, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.
 26. The method of claim 1further comprising a bioactive agent.
 27. The method of claim 26 whereinthe bioactive agent is selected from paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutses, superoxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.
 28. The method of claim 1wherein the chemo-attractant comprises a receptor binding to ICAM(intercellular adhesion molecule) molecules or VCAM (vascular celladhesion molecule) molecules present in the endothelial cells.
 29. Themethod of claim 28 wherein the medical device is a bioabsorbable stent.30. The method of claim 29 further comprising a bioactive agent.
 31. Themethod of claim 30 wherein the bioactive agent is selected frompaclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxidedonors, super oxide dismutses, super oxide dismutase mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.
 32. The method of claim 1wherein the medical device is a bioabsorbable stent.
 33. The method ofclaim 32 further comprising a bioactive agent.
 34. The method of claim33 wherein the bioactive agent is selected from paclitaxel, docetaxel,estradiol, 17-beta-estradiol, nitric oxide donors, super oxidedismutses, super oxide dismutase mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,mometasone, pimecrolimus, imatinib mesylate, or midostaurin, orprodrugs, co-drugs, or combinations of these.